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Magnetic Nanoworms and Nanocrystals Deliver siRNA to Tumors

Small pieces of nucleic acid known as short interfering RNA, or siRNA, can disable the production of specific proteins, a property that makes them one of the most promising new classes of anticancer drugs in development. In fact, at least two siRNA-based therapies against cancer, both delivered to tumors in nanoparticles, have begun human clinical trials.

Now researchers at the Massachusetts Institute of Technology (MIT) have developed a modular nanoparticle-based drug delivery system that maximizes the amount of siRNA molecules that can not only enter cells but can also escape into the cytoplasm, where it can interfere with protein production. Sangeeta Bhatia, MD, Ph.D., and Phillip A. Sharp, Ph.D., MIT-Harvard Center of Cancer Nanotechnology Excellence, and Alain Jean Charest, Ph.D., M.Sc., Tufts University School of Medicine, led the study, whose findings appear in the journal ACS Nano .

The new siRNA delivery vehicle is conjugated dendrimers and fluorescent magnetic nanoworms researchers call “dendriworms. Dendrimers are synthetic polymers that generally have a spherical shape and can be easily modified to carry a large variety of molecules including nucleic acids. In this study, Dr. Bhatia and colleagues used polyamidoamine dendrimers, a large amount of preclinical work has shown completely biocompatible, and next to a chain of magnetic nanoparticles known as nanoworm. The researchers also added a fluorescent molecule to the nanoworms, creating a drug delivery vehicle that could also image the body using magnetic resonance imaging or fluorescence imaging. In a final step, the researchers added the dendriworms siRNA. The result of the building, containing approximately 7 magnetic nanoparticles, 45-50 dendrimers, and 50 siRNA molecules remained stable under test conditions up to 6 hours.

When added to cells growing in culture, this siRNA complex dendrimer rapidly entered the cells and then leaks into the cytoplasm. The researchers found no significant toxicity in these experiments in vitro. Dendriworms When administered to human glioblastoma cells, was capable of delivering siRNA to silence specific gene production, in this case, a mutant gene known to be involved in the development of glioblastoma.

Dendriworm To test whether this would work in a living animal, the researchers used a strain of mice that were genetically engineered to develop tumors spontaneously glioblastoma in the brain. The researchers found that the dendriworms were able to penetrate tumors, deliver your cargo therapeutic siRNA in the tumor cells and silence the gene in target cells.

Meanwhile, a group of researchers at the Jikei University School of Medicine in Tokyo, Japan, led by Yoshihisa Namiki, MD, has shown that lipid-coated magnetic crystals can safely and effectively deliver therapeutic siRNA to tumors in mice. The results of their experiments were published in the journal Nature Nanotechnology.

Dr. Namiki and colleagues created their delivery vehicle for iron oxide nanocrystals coated with a layer of positively charged lipids. This layer is highly bound to siRNA molecules, which, as all nucleic acids, have a strong negative charge. After optimization of the lipid layer to maximize efficiency in delivery of siRNA, researchers used nanoparticles to deliver their anti-EGFR siRNA in gastric tumors in mice. After injecting the mice with therapeutic nanoparticles, the researchers applied a local magnetic field around the vicinity of the tumor. After 28 days, tumors in the treated mice were 50% smaller compared with tumors in mice treated with nanoparticles and not just the siRNA.

Working with dendriworms, which is detailed in the document of “functional delivery of siRNA in mice dendriworms” was supported by the NCI Alliance for Nanotechnology in Cancer, a global initiative designed to accelerate the application of nanotechnology to prevention, diagnosis and treatment of cancer. Researchers at Brigham and Women’s Hospital, also participated in this study. A summary is available on the website of the magazine.

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